The adrenergic nervous control of bodily functions is mediated by two hormones: norepinephrine, which is generated in the adrenergic nerves and released from their endings, and epinephrine, which is synthesized in the adrenal medulla and secreted into circulating blood. Both of these hormones act by binding to special receptors, designated as "adrenergic" receptors, which mediate the signal of the hormones to the intracellular biochemical mechanisms leading to stimulation of diverse physiological functions. Such functions include contraction of vascular smooth muscle (which can increase blood pressure), acceleration of heart rate, induction of metabolic changes in the liver, modulation of central nervous system activity, and many others.
The adrenergic receptors are proteins embedded in cellular membranes having unique, specific amino acid sequences. Four general families of adrenergic receptors have been identified and designated .alpha..sub.1, .alpha..sub.2, .beta..sub.1 and .beta..sub.2, all of which can be stimulated by norepinephrine and epinephrine. These receptor families, however, differ such that specific agents have been developed which can selectively stimulate or inhibit each type of receptor. The degree and type of receptor selectivity for a particular agonist or antagonist agent is an important pharmacological property of such an agent and can have substantial impact on its biological activity, side effects and safety. In general, excessive stimulation of the .alpha..sub.1 adrenoreceptor is a hallmark of numerous pathological situations and disease states such as hypertension, congestive heart failure, cardiac hyperplasia, benign prostatic hyperplasia, hyperinsulinemia, lipid disorders, impotency, as well as many others.
Importantly, the .alpha..sub.2 adrenoreceptors, which are very similar to the .alpha..sub.1 species, regulate the release of the two adrenergic hormones, norepinephrine and epinephrine, and impact on the overall level of adrenergic activity. The stimulation of .alpha..sub.2 receptors by an agonist inhibits the secretion of norepinephrine and epinephrine, whereas .alpha..sub.2 antagonist activity increases the secretion of these hormones substantially. Thus, the .alpha..sub.1 /.alpha..sub.2 adrenoreceptor selectivity of an .alpha.-antagonist is very important and a desirable feature.
A number of non-selective .alpha.-adrenergic blockers, such as phenoxybenzamine and phentolamine, have prominent effects on both .alpha..sub.1 and .alpha..sub.2 receptors. It is the .alpha..sub.2 component of their adrenergic receptor activity which increases the adrenergic hormone secretion and thus limits their therapeutic use. Typical of such .alpha..sub.2 antagonist effects are increases in plasma catecholamine levels, increases in heart rate and contractility, and other highly undesirable therapeutic phenomena.
It is therefore desirable to obtain .alpha..sub.1 blocking agents which have greater .alpha..sub.1 /.alpha..sub.2 selectivity than agents currently available. Such selectivity permits treatment of diseases characterized by elevated .alpha..sub.1 adrenergic activity without stimulating .alpha..sub.2 adrenoreceptor-mediated secretion of norepinephrine and epinephrine.
2-[4[(Tetrahydro-2-furanyl)carbonyl]-1-piperazinyl]-6,7-dimethoxy-4-quinazo linamine, also commonly known by its generic name, terazosin, has been known for several years as an antihypertensive drug. U.S. Pat. No. 4,026,894 discloses and claims the compound and U.S. Pat. No. 4,112,097 discloses and claims pharmaceutical compositions containing the compound and a method of treating hypertension in mammals. U.S. Pat. No. 4,251,532 discloses and claims the dihydrate of the hydrochloride salt of terazosin. The latter patent also discloses and claims pharmaceutical compositions comprising the hydrochloride dihydrate and a method of treating hypertension. While the terazosin molecule possesses a single chiral center, and can thus exist in two enantiomeric forms, none of these patents discusses this optical property of the molecule or mentions the two enantiomers.
In 1987, Nagatomo and coworkers reported the binding of the racemic compound and the individual enantiomers to .alpha.-receptors in dog brain and aorta tissue (Nagatomo, et al., Chem. Pharm. Bull., 35(4): 1629-1632 (1987)). Their data indicate that, while both enantiomers and the racemic compound bind selectively to the .alpha..sub.1 receptors, little difference appeared to exist between the degrees of selectivity of the two enantiomers for .alpha..sub.1 receptors over .alpha..sub.2 receptors. This article did not report any data to indicate the optical purity of the materials employed.